The bioavailability of sparingly water-soluble drugs is well-known to be limited and to be profoundly affected by such factors as the fed state of the patient, the rate of metabolism in relation to the rate of absorption in the gastrointestinal (GI) tract, and the dosage form. Many attempts have been made to improve the form of dosage for such low solubility drugs, generally with the aim to improving the bioavailability of such drugs. Most such formulations were immediate release in nature as this generally maximizes the amount of drug absorbed. In a few cases, sustained or delayed release dosage forms have been formulated with a view to attaining a constant rate of release of the drug in the gut over a sufficiently sustained period of time. However, most such attempts have been unsuccessful, resulting in dosage forms that generally either provide immediate release only or poor bioavailability.
Exemplary sustained release dosage forms have included an osmotic tablet comprising a semipermeable wall surrounding a compartment containing the drug and a layer of swellable hydrogel, with the crystalline drug being delivered through a passageway in the semipermeable wall by swelling of the hydrogel, as described in U.S. Pat. No. 4,327,725; another osmotic tablet comprising a wall permeable to an exterior fluid but impermeable to the drug, the wall surrounding a compartment containing two osmotic agents, two expandable polymers and the drug, as described in U.S. Pat. No. 4,612,008; drug dispersed in a swellable hydrogel matrix core that releases the drug by diffusion into the environment of use, as described in U.S. Pat. No. 4,624,848; a hydrogel reservoir containing a multiplicity of tiny pills wherein each tiny pill consists of a wall surrounding a drug core, as described in U.S. Pat. No. 4,851,232; and a two-layered tablet wherein one layer is drug mixed with a hydrogel and the other layer is a hydrogel, as described in U.S. Pat. No. 5,516,527. One sustained release dosage form consists of a coated tablet with a core of a solid dispersion of drug in a swellable polyoxamer hydrogel that releases the drug by diffusion from the swollen tablet mass and by erosion of the tablet surface, as described in PCT Application No. 97/02017.
Solid dispersion dosage forms may be formed by solvent evaporation, by spray drying, by spraying drug solution onto the carrier in a fluidized bed granulator, by twin screw extrusion, by melt fusion, by mechanical admixture such as by ball milling and by mechanical admixture at an elevated but non-melting temperature. See, for example, PCT Application No. 93/11749; European Patent Application No. 0 552 708; U.S. Pat. No. 5,456,923; Chowdary et al., 32 Indian Drugs 477 (1995); Dangprasirt et al., 21 Drug Development and Ind. Pharm. 2323 (1995); and Goracinova et al., 22 Drug Development and Ind. Pharm. 255 (1996).
However, such solid dispersion drug delivery systems have achieved very limited success in delivering poorly water-soluble drugs as they generally tend to be immediate release forms having those forms"" inherent drawbacks of high peak drug concentrations in the blood, short times following administration when drug concentrations in the blood reach a maximum (xe2x80x9ctmaxxe2x80x9d) and relatively short duration of effective levels of concentration in the blood. In addition, although improved bioavailability relative to crystalline drug is reported, bioavailability for such dosage forms is nevertheless often low in an absolute sense. Specifically, such drug delivery systems often exhibit little overall improvement in the concentration of drug in a patient""s blood over a given time period (commonly referred to as xe2x80x9cAUCxe2x80x9d in reference to the calculation of the area under a curve comprising a plot of concentration of drug against time).
In the case of the solid polyoxamer dispersion dosage form reported in PCT 97/02017, the dosage form suffers either from slow and incomplete release in cases when drug is released by diffusion through a membrane coating due to the inherent low solubility of the drug; conversely, where drug is released from such a dosage form by erosion of the polyoxamer, drug release is non-zero order and variable, being dependent on the patient""s fed state and gastric retention time. In addition, since the polyoxamer dispersion polymers disclosed are highly hydrophilic and generally require aqueous solvents for dissolution, these polymers cannot be used to form dispersions with hydrophobic drugs via solvent processing as it is difficult or impossible to dissolve the drug and polymer in a common solvent.
There is therefore still a need in the art for a controlled release dosage form for delivery of a low solubility drug with a short elimination half-life that provides improved drug bioavailability. These needs and others which will become apparent to one skilled in the art are met by the present invention, which is summarized and described in detail below.
The present invention comprises a controlled release dosage form having two components: (a) a core containing a low solubility drug in the form of an amorphous solid dispersion; and (b) a non-dissolving and non-eroding coating surrounding the core, the coating controlling the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion of some or all of the core to the environment of use. At least a major portion of the drug, i.e., at least about 60% is amorphous (as opposed to crystalline). More preferably, substantially all of the drug, i.e., at least about 75%, is amorphous. Most preferably, essentially all of the drug, i.e., at least about 90% is amorphous. The term xe2x80x9cdrugxe2x80x9d is conventional, denoting a compound having beneficial, prophylactic, and/or therapeutic properties when administered to an animal, especially a human.